Nobiletin, a major polymethoxy flavone, has been demonstrated to exert protective effects on cardivascular diseases. However, the effects of nobiletin on pulmonary arterial hypertension (PAH) have not been studied. Herein in this report, PAH was induced by a single monocrotaline (MCT) injection in rats, and then rats were treated with nobiletin for consecutive three weeks. At the end of three weeks, hemodynamic parameters, right ventricular hypertrophy and pulmonary vascular remodeling were assessed. Moreover, we evaluated anti-proliferative effect of nobiletin in vivo and in vitro. Nobiletin effectively reduced right ventricular systolic pressure (RVSP) and attenuated right ventricular hypertrophy and medial wall thickening in MCT-treated rats. Furthermore, nobiletin inhibited Src/STAT3 activation in the lungs of PAH rats. In rat pulmonary artery smooth muscle cells (PASMCs), nobiletin suppressed PDGF-BB-induced rat PASMCs proliferation and Src/STAT3 activation, accompanied with down-regulation of downstream targets Pim1 and NFATc2. Taken together, our data indicated that nobiletin may exert protective effects on PAH via the inhibition of PASMCs proliferation and Src/STAT3 activation.